SLE: Genetic Risk for Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic, long-term inflammation (1). Women are affected more than men (>8:1) (3), and the average diagnosis is between ages 10 and 50. Common symptoms of SLE are summarized in Figure 1, and in brief are: joint pain and swelling, fatigue, sensitivity to light, a butterfly skin rash, nausea, and fingers that change color when cold (1). There is currently no cure for SLE, although treatment options include drugs for pain and nausea management as well as corticosteroids to manage severe symptom flares (1). The cause of SLE is still unknown. The first reported cases of "lupus" autoimmune diseases date back to 1817, when Dr. Laurent Biett described a disease characterized by destruction of tissue. Then, doctors were describing several diseases including lupus vulgaris, a painful form of skin tuberculosis. Today we know that lupus vulgaris and SLE are two very different diseases (2). The first genome-wide association studies for SLE were performed in the late 1990's. Today, there are 250 genome wide association articles related to SLE (Pubmed search, GWAS, SLE). Genetics of SLE Genetic associaion of SLE have focused on defects in the immune system. Since SLE is autoimmune, there are numerous pathways that could be involved. As of 1996, what was known about genetic susceptibility in characterized in a figure by Kotzin shown in Figure 2 (3). Associations may be found in CD4 T cell development, B cell development, antibody production and may include still unknown environmental triggers. Recent SLE work (from GWAS and others) has implicated molecular targets such as the complement pathway, HLA genes, FCgamma receptors and TNF (tumor necrosis factor), PARP (poly-ADP ribosylase-1), and the signaling lymphocyte activation marker (SLAM) gene locus (4, 5) as genetic susceptibility markers for SLE. SLAM family receptors (SLAMf1 thru SLAMf9) are expressed on the surfaces of B and T cells and are instrumental in formation of germinal centers in the lymph node and T and B cell signaling interactions (5). This family, along with downstream signaling effector molecules such as the SLAM-associated protein (SAP) could be important in SLE pathogenesis. GWAS: Genome Scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African American pedigrees In a study in 1998 by Moser et al, 533 total subjects were screened for genetic linkage to SLE. Two-hundred-twenty patients were affected with SLE and the data represented 94 families. Of those families, 31 were African American while 55 were of European-American descent. For analysis, any marker that obtained a LOD score of >1.5 was evaluated. Genotyping was performed using 312 microsatellite markers. Analyses included linkage analysis , parametric , and nonparametric analysis (statistical analysis described in a paper by the Whitehead Institute (6)). The results of this study showed 16 possible loci for SLE susceptibility summarized in Figure 3. Of those markers, the chromosome location of 1q23 was linked to SLE, a location corroborated in many other GWAS SLE studies (7, 8). Also located at chromosome 1q23 is the SLAM gene locus (8). Association of Ly9 (SLAMf3) in UK and Canadian SLE families In a study by Graham et al, the association of the 1q23 locus and SLE was further confirmed on chromosome 1. Not only had this linkage site been shown in numerous genome-wide studies, but it also was shown to be a susceptibility gene in several mouse models of lupus. Herein, the authors screened 2 family collections for markers across the SLAM family gene locus on chromosome 1 (8). Family collections from the UK and Canada were screened across the 1q23 gene location. Both families were found to have SLAMf7 and SLAMf3 (Ly9) genetic association. The results of the study are summarized in Figure 4. Families were genotyped and then subjected to a transmission disequilibrium test (TDT)-- a family based association test for genetic linkage (8). The final results of the study implicate members of the SLAM family, particularly SLAMf7 and SLAMf3 as genetic linkage markers, indicating a function for B and T cell involvment. Progress from GWAS Studies In 1996, little was known about the genetics of SLE. Kotzin et al. published a diagram of possible pathways and gene targets. Today, much more is known with upwards of 26 genes in regulation pathways identified as genetic linkage markers (9). Figure 5 summarizes the known genetic linkage markers from GWAS studies with a significance of (p<5x10^-8). This data suggests many linkage loci associated with not only SLE, but several other autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis (PS) (9). While there is no clear causative target, the amount of data generated on SLE in recent years have allowed a breadth of knowledge on the intricate pathways involved in autoimmunity. References 1. National Library of Medicine and National Institutes of Health. Medline Plus. "Systemic lupus erythematosus." http://www.nlm.nih.gov/medlineplus/ency/article/000435.htm 2. Fatovic-Ferencic and Holubar. "Early history and inconography of lupus erthymatosus." (2004). Clinics in Dermatology. PMID: 15234009 Article: http://www.sciencedirect.com/science/article/pii/S0738081X03001354 3. Kotzin, Brian. "Systemic Lupus Erythematosus." (1996). Cell. http://www.sciencedirect.com/science/article/pii/S0092867400811083 4. Wakeland et al. "Delineating the Genetic Basis of Systemic Lupus Erythematosus." (2001). Immunity. Volume 15, Issue 3, Pages 397-408 Article: http://www.sciencedirect.com/science/article/pii/S1074761301002011 5. Wang, Batteux, Wakeland. "The role of SLAM/CD2 polymorphisms in systemic autoimmunity." (2010). Current Opinion in Immunology. PMID: 21094032 6. Kruglyak, L et al. "Parametric and Nonparametric linkage analysis: a unified multipoint approach." American Journal of Human Genetics. 1996. Jun; 58(6): 1347-63 PMID: 8651312 7. Moser et al. "Genome scane of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African American pedigrees." (1998). Proc Natl Acad Sci. 95(25) 14869-14874. PMID: 9843982 8. Graham et al. "Association of Ly9 in UK and Canadian SLE Families." (2008). Genes and Immunity. Volume 9:93-102 PMID:18216865 9. Chui et al. "Genetic susceptibility to SLE: Recent progress from GWAS."'' Journal of Autoimmunity''. (2013) Volume 41, Pages 25-33 PMID: 23395425